Compelling evidence implicates reactive oxygen species (ROS) in causing neuronal and cardiovascular dysfunction in atherosclerosis and aging. The goals of the proposed project are to define the role of ROS in causing baroreflex dysfunction in these states and to determine effects of combined atherosclerosis and aging on baroreflex sensitivity. The first hypothesis to be tested is that ROS impair baroreflex function through differential effects on afferent and central components of the reflex. The defect may be primarily in the afferent limb in atherosclerosis, whereas both components may be impaired in aging. The relative importance of alterations in afferent and central components of the baroreflex in atherosclerotic and senescent mice will be determined through direct recordings of aortic depressor nerve activity, renal sympathetic nerve activity, arterial pressure and heart rate; and measurement of responses to drug-induced changes in arterial pressure and electrical stimulation ofbaroreceptor afferents in the aortic depressor nerve. The role of ROS will be assessed through treatment with membrane permeable superoxide dismutase/catalase mimetics and by studies of genetically-modified mice deficient in antioxidant molecules (e.g. MnSOD and CuZnSOD) and transgenics that over-express antioxidant enzymes. The second hypothesis to be tested is that the mechanism of the ROS-mediated decrease in baroreceptor sensitivity differs in atherosclerosis and aging. Vascular NAD(P)H oxidase is proposed as the source of ROS in atherosclerosis while mitochondria in baroreceptors are proposed as the source in aging. Studies in genetically-modified mice, adenoviral-mediated gene transfer, and pharmacological antagonists will enable selective manipulation of ROS in subcellular compartments in specific cell types to reveal the sources of ROS generation. Furthermore, neuronal ROS generation and its effects on membrane excitability and ionic currents will be directly assessed in studies of cultured baroreceptor neurons isolated from control, atherosclerotic and senescent mice. The proposed studies are expected to have important implications for understanding mechanisms of baroreflex dysfunction in patients with atherosclerosis and in the elderly. The results may be particularly relevant to humans where atherosclerosis is common in the elderly. Antioxidant therapies are currently receiving much attention as promising agents in the prevention and treatment of cardiovascular disease. Knowledge gained from the proposed studies may impact on future use of antioxidant therapies.